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Dual inhibition of HDAC and EGFR signaling with CUDC-101 induces potent suppression of tumor growth and metastasis in anaplastic thyroid cancer.

ABSTRACT: Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies that currently has no effective therapy. We performed quantitative high-throughput screening (qHTS) in three ATC cell lines using 3,282 clinically approved drugs and drug candidates, and identified 100 active agents. Enrichment analysis of active compounds showed that inhibitors of EGFR and histone deacetylase (HDAC) were most active. Of these, the first-in-class dual inhibitor of EGFR, HER2 and HDACs, CUDC-101, had the highest efficacy and lower IC50 than established drugs. We validated that CUDC-101 inhibited cellular proliferation and resulted in cell death by inducing cell cycle arrest and caspase-dependent apoptosis. CUDC-101 also inhibited cellular migration in vitro. Mechanistically, CUDC-101 inhibited MAPK signaling and histone deacetylation in ATC cell lines with multiple driver mutations present in human ATC. The anticancer effect of CUDC-101 was associated with increased expression of p21 and E-cadherin, and reduced expression of survivin, XIAP, ?-catenin, N-cadherin, and Vimentin. In an in vivo mouse model of metastatic ATC, CUDC-101 inhibited tumor growth and metastases, and significantly prolonged survival. Response to CUDC-101 treatment in vivo was associated with increased histone 3 acetylation and reduced survivin expression. Our findings provide a preclinical basis to evaluate CUDC-101 therapy in ATC.

SUBMITTER: Zhang L

PROVIDER: S-EPMC4496203 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Dual inhibition of HDAC and EGFR signaling with CUDC-101 induces potent suppression of tumor growth and metastasis in anaplastic thyroid cancer.

Zhang Lisa L Zhang Yaqin Y Mehta Amit A Boufraqech Myriem M Davis Sean S Wang Jing J Tian Ze Z Yu Zhiya Z Boxer Matthew B MB Kiefer Jeffrey A JA Copland John A JA Smallridge Robert C RC Li Zhuyin Z Shen Min M Kebebew Electron E

Oncotarget 20150401 11

Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies that currently has no effective therapy. We performed quantitative high-throughput screening (qHTS) in three ATC cell lines using 3,282 clinically approved drugs and drug candidates, and identified 100 active agents. Enrichment analysis of active compounds showed that inhibitors of EGFR and histone deacetylase (HDAC) were most active. Of these, the first-in-class dual inhibitor of EGFR, HER2 and HDACs, CUDC-101, had the ...[more]

PMID: 25940539

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Project description:Pancreatic cancer has a poor prognosis. New treatment options are urgently required to improve patient outcomes. One promising new class of anticancer drugs are synthetic histone deacetylase inhibitors (HDACi) which modulate chromatin structure and gene expression by blocking histone deacetylation. In this study, we aimed at comparing the in vitro capacities of the HDACi SAHA and CUDC-101 to increase radiosensitivity of human pancreatic tumor cell lines. Therefore, three pancreatic cancer cell lines (Su.86.86, MIA Paca-2, T3M-4) were treated with SAHA (1.5-5 µM) or CUDC-101 (0.25-3 µM) and after 24 h irradiated. Cell proliferation, clonogenic survival and apoptosis was determined. Additionally, cell lysates were investigated for the expression of apoptosis-related proteins. CUDC-101 and SAHA increased the radiation sensitivity of pancreatic tumor cell lines in a dose-dependent manner. This was evidenced by cell proliferation and clonogenic survival. Furthermore, enhanced radiation sensitivity after CUDC-101 or SAHA treatment was confirmed for Su.86.86 and T3M-4 cells in a 3-D microtissue approach. Increased amounts of subG1 cells and diminished full length PARP-1 suggest increased radiation-induced apoptosis after SAHA or CUDC-101 treatment. The comparison of both inhibitors in these assays manifested CUDC-101 as more potent radiosensitizer than SAHA. In line, western blot quantification of the apoptosis-inhibitory proteins XIAP and survivin showed a stronger down-regulation in response to CUDC-101 treatment than after SAHA application. These proteins may contribute to the synergy between HDAC inhibition and radiation response. In conclusion, these preclinical results suggest that treatment with the HDAC inhibitors CUDC-101 or SAHA can enhance radiation-induced cytotoxicity in human pancreatic cells. However, comparison of both inhibitors identified the multi target inhibitor CUDC-101 as more potent radiosensitizer than the HDAC inhibitor SAHA.

Dataset Information

Dual inhibition of HDAC and EGFR signaling with CUDC-101 induces potent suppression of tumor growth and metastasis in anaplastic thyroid cancer.

Publications

Dual inhibition of HDAC and EGFR signaling with CUDC-101 induces potent suppression of tumor growth and metastasis in anaplastic thyroid cancer.

Similar Datasets

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